EP0845986A1 - Composition pharmaceutique contenant du 3-(2,2,2-trimethylhydrazinium) propionate et de la gamma-butyrobetaine, destinees au traitement des maladies cardiovasculaires - Google Patents

Composition pharmaceutique contenant du 3-(2,2,2-trimethylhydrazinium) propionate et de la gamma-butyrobetaine, destinees au traitement des maladies cardiovasculaires

Info

Publication number: EP0845986A1
Authority: EP; European Patent Office
Prior art keywords: pharmaceutical composition; composition according; butyrobetaine; pharmaceutically acceptable; active principle
Prior art date: 1995-08-21
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Granted

Application number

EP96927931A

Other languages

German (de)

English (en)

Other versions

EP0845986B1 (fr

Inventor

Ivars Kalvinsh

Maris Veveris

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Grindeks JSC

Original Assignee

Individual

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1995-08-21

Filing date

1996-08-20

Publication date

1998-06-10

1996-08-20 Application filed by Individual filed Critical Individual

1998-06-10 Publication of EP0845986A1 publication Critical patent/EP0845986A1/fr

2003-04-02 Application granted granted Critical

2003-04-02 Publication of EP0845986B1 publication Critical patent/EP0845986B1/fr

2016-08-20 Anticipated expiration legal-status Critical

Status Expired - Lifetime legal-status Critical Current

Links

239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 28
XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 title claims abstract description 25
208000024172 Cardiovascular disease Diseases 0.000 title claims abstract description 5
JHPNVNIEXXLNTR-UHFFFAOYSA-O 4-(trimethylammonio)butanoic acid Chemical compound C[N+](C)(C)CCCC(O)=O JHPNVNIEXXLNTR-UHFFFAOYSA-O 0.000 title abstract 2
239000000203 mixture Substances 0.000 claims abstract description 8
238000011282 treatment Methods 0.000 claims abstract description 7
239000003937 drug carrier Substances 0.000 claims abstract 6
JHPNVNIEXXLNTR-UHFFFAOYSA-N 4-(trimethylammonio)butanoate Chemical compound C[N+](C)(C)CCCC([O-])=O JHPNVNIEXXLNTR-UHFFFAOYSA-N 0.000 claims description 58
239000000126 substance Substances 0.000 claims description 16
239000000243 solution Substances 0.000 claims description 7
238000002347 injection Methods 0.000 claims description 6
239000007924 injection Substances 0.000 claims description 6
239000002904 solvent Substances 0.000 claims description 5
-1 aromatizers Substances 0.000 claims description 4
239000002775 capsule Substances 0.000 claims description 4
239000008298 dragée Substances 0.000 claims description 4
239000008187 granular material Substances 0.000 claims description 4
239000000843 powder Substances 0.000 claims description 4
239000003826 tablet Substances 0.000 claims description 4
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
239000007894 caplet Substances 0.000 claims description 3
239000008103 glucose Substances 0.000 claims description 3
WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
239000007853 buffer solution Substances 0.000 claims description 2
239000012153 distilled water Substances 0.000 claims description 2
239000002674 ointment Substances 0.000 claims description 2
239000011505 plaster Substances 0.000 claims description 2
239000000829 suppository Substances 0.000 claims description 2
239000006188 syrup Substances 0.000 claims description 2
235000020357 syrup Nutrition 0.000 claims description 2
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims 4
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 4
229920001223 polyethylene glycol Polymers 0.000 claims 3
235000015112 vegetable and seed oil Nutrition 0.000 claims 3
239000008158 vegetable oil Substances 0.000 claims 3
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 2
239000003995 emulsifying agent Substances 0.000 claims 2
239000003925 fat Substances 0.000 claims 2
235000019197 fats Nutrition 0.000 claims 2
235000011187 glycerol Nutrition 0.000 claims 2
239000003381 stabilizer Substances 0.000 claims 2
229910002012 Aerosil® Inorganic materials 0.000 claims 1
GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims 1
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims 1
229920000168 Microcrystalline cellulose Polymers 0.000 claims 1
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims 1
229920002472 Starch Polymers 0.000 claims 1
229930006000 Sucrose Natural products 0.000 claims 1
CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims 1
239000002253 acid Substances 0.000 claims 1
239000003086 colorant Substances 0.000 claims 1
235000013681 dietary sucrose Nutrition 0.000 claims 1
235000019441 ethanol Nutrition 0.000 claims 1
239000000796 flavoring agent Substances 0.000 claims 1
235000013355 food flavoring agent Nutrition 0.000 claims 1
235000001727 glucose Nutrition 0.000 claims 1
239000000644 isotonic solution Substances 0.000 claims 1
239000008101 lactose Substances 0.000 claims 1
235000019813 microcrystalline cellulose Nutrition 0.000 claims 1
239000008108 microcrystalline cellulose Substances 0.000 claims 1
229940016286 microcrystalline cellulose Drugs 0.000 claims 1
238000007911 parenteral administration Methods 0.000 claims 1
239000002861 polymer material Substances 0.000 claims 1
150000003839 salts Chemical class 0.000 claims 1
235000019698 starch Nutrition 0.000 claims 1
239000008107 starch Substances 0.000 claims 1
229960004793 sucrose Drugs 0.000 claims 1
239000000454 talc Substances 0.000 claims 1
229910052623 talc Inorganic materials 0.000 claims 1
235000012222 talc Nutrition 0.000 claims 1
230000001225 therapeutic effect Effects 0.000 abstract description 3
231100000053 low toxicity Toxicity 0.000 abstract description 2
238000007920 subcutaneous administration Methods 0.000 abstract 1
230000000694 effects Effects 0.000 description 14
210000004165 myocardium Anatomy 0.000 description 9
206010003119 arrhythmia Diseases 0.000 description 8
230000006793 arrhythmia Effects 0.000 description 8
208000028867 ischemia Diseases 0.000 description 8
230000017531 blood circulation Effects 0.000 description 7
238000002474 experimental method Methods 0.000 description 7
230000033764 rhythmic process Effects 0.000 description 7
UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 6
UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 6
210000004204 blood vessel Anatomy 0.000 description 6
238000001802 infusion Methods 0.000 description 6
PHIQHXFUZVPYII-ZCFIWIBFSA-O (R)-carnitinium Chemical compound C[N+](C)(C)C[C@H](O)CC(O)=O PHIQHXFUZVPYII-ZCFIWIBFSA-O 0.000 description 5
241001465754 Metazoa Species 0.000 description 5
241000699670 Mus sp. Species 0.000 description 5
241000700159 Rattus Species 0.000 description 5
230000009471 action Effects 0.000 description 5
230000015572 biosynthetic process Effects 0.000 description 5
229960004203 carnitine Drugs 0.000 description 5
231100000518 lethal Toxicity 0.000 description 5
230000001665 lethal effect Effects 0.000 description 5
230000010410 reperfusion Effects 0.000 description 5
OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 4
239000013543 active substance Substances 0.000 description 4
230000036772 blood pressure Effects 0.000 description 4
239000001110 calcium chloride Substances 0.000 description 4
229910001628 calcium chloride Inorganic materials 0.000 description 4
LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 4
230000002861 ventricular Effects 0.000 description 4
206010061216 Infarction Diseases 0.000 description 3
240000007711 Peperomia pellucida Species 0.000 description 3
208000005392 Spasm Diseases 0.000 description 3
230000002526 effect on cardiovascular system Effects 0.000 description 3
230000007574 infarction Effects 0.000 description 3
230000000144 pharmacologic effect Effects 0.000 description 3
238000002360 preparation method Methods 0.000 description 3
230000000069 prophylactic effect Effects 0.000 description 3
238000011285 therapeutic regimen Methods 0.000 description 3
JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 2
241000282326 Felis catus Species 0.000 description 2
MRAUNPAHJZDYCK-BYPYZUCNSA-N L-nitroarginine Chemical compound OC(=O)[C@@H](N)CCCNC(=N)N[N+]([O-])=O MRAUNPAHJZDYCK-BYPYZUCNSA-N 0.000 description 2
208000007101 Muscle Cramp Diseases 0.000 description 2
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
229960004373 acetylcholine Drugs 0.000 description 2
230000003288 anthiarrhythmic effect Effects 0.000 description 2
239000003416 antiarrhythmic agent Substances 0.000 description 2
206010061592 cardiac fibrillation Diseases 0.000 description 2
LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 2
201000010099 disease Diseases 0.000 description 2
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
230000002600 fibrillogenic effect Effects 0.000 description 2
238000010253 intravenous injection Methods 0.000 description 2
231100000225 lethality Toxicity 0.000 description 2
PVBQYTCFVWZSJK-UHFFFAOYSA-N meldonium Chemical compound C[N+](C)(C)NCCC([O-])=O PVBQYTCFVWZSJK-UHFFFAOYSA-N 0.000 description 2
238000011321 prophylaxis Methods 0.000 description 2
229960001404 quinidine Drugs 0.000 description 2
230000029058 respiratory gaseous exchange Effects 0.000 description 2
239000011780 sodium chloride Substances 0.000 description 2
210000003462 vein Anatomy 0.000 description 2
102100022715 Acetyl-coenzyme A thioesterase Human genes 0.000 description 1
206010002091 Anaesthesia Diseases 0.000 description 1
206010002383 Angina Pectoris Diseases 0.000 description 1
239000004475 Arginine Substances 0.000 description 1
102000000476 Fatty Acid Transport Proteins Human genes 0.000 description 1
108010055870 Fatty Acid Transport Proteins Proteins 0.000 description 1
229940122224 Gamma butyrobetaine hydroxylase inhibitor Drugs 0.000 description 1
101000678862 Homo sapiens Acetyl-coenzyme A thioesterase Proteins 0.000 description 1
206010020772 Hypertension Diseases 0.000 description 1
206010023644 Lacrimation increased Diseases 0.000 description 1
208000009525 Myocarditis Diseases 0.000 description 1
KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical class C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 1
102000008299 Nitric Oxide Synthase Human genes 0.000 description 1
108010021487 Nitric Oxide Synthase Proteins 0.000 description 1
241000700157 Rattus norvegicus Species 0.000 description 1
206010039424 Salivary hypersecretion Diseases 0.000 description 1
206010047139 Vasoconstriction Diseases 0.000 description 1
230000004913 activation Effects 0.000 description 1
230000007059 acute toxicity Effects 0.000 description 1
231100000403 acute toxicity Toxicity 0.000 description 1
238000001949 anaesthesia Methods 0.000 description 1
230000037005 anaesthesia Effects 0.000 description 1
238000010171 animal model Methods 0.000 description 1
210000000709 aorta Anatomy 0.000 description 1
239000008280 blood Substances 0.000 description 1
210000004556 brain Anatomy 0.000 description 1
230000000747 cardiac effect Effects 0.000 description 1
230000003293 cardioprotective effect Effects 0.000 description 1
210000000748 cardiovascular system Anatomy 0.000 description 1
210000001715 carotid artery Anatomy 0.000 description 1
OJYGBLRPYBAHRT-IPQSZEQASA-N chloralose Chemical compound O1[C@H](C(Cl)(Cl)Cl)O[C@@H]2[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]21 OJYGBLRPYBAHRT-IPQSZEQASA-N 0.000 description 1
229950009941 chloralose Drugs 0.000 description 1
210000004351 coronary vessel Anatomy 0.000 description 1
239000006196 drop Substances 0.000 description 1
239000000945 filler Substances 0.000 description 1
230000001435 haemodynamic effect Effects 0.000 description 1
239000012535 impurity Substances 0.000 description 1
238000002955 isolation Methods 0.000 description 1
230000004317 lacrimation Effects 0.000 description 1
230000004807 localization Effects 0.000 description 1
150000004668 long chain fatty acids Chemical class 0.000 description 1
230000007246 mechanism Effects 0.000 description 1
230000010534 mechanism of action Effects 0.000 description 1
229960002937 meldonium Drugs 0.000 description 1
239000012528 membrane Substances 0.000 description 1
230000004060 metabolic process Effects 0.000 description 1
238000000034 method Methods 0.000 description 1
150000004702 methyl esters Chemical class 0.000 description 1
210000003470 mitochondria Anatomy 0.000 description 1
231100000404 nontoxic agent Toxicity 0.000 description 1
230000036581 peripheral resistance Effects 0.000 description 1
DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
229960002695 phenobarbital Drugs 0.000 description 1
230000009090 positive inotropic effect Effects 0.000 description 1
230000008569 process Effects 0.000 description 1
230000002035 prolonged effect Effects 0.000 description 1
230000001681 protective effect Effects 0.000 description 1
230000010344 pupil dilation Effects 0.000 description 1
208000026451 salivation Diseases 0.000 description 1
230000002048 spasmolytic effect Effects 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
239000000758 substrate Substances 0.000 description 1
230000002195 synergetic effect Effects 0.000 description 1
238000003786 synthesis reaction Methods 0.000 description 1
231100000331 toxic Toxicity 0.000 description 1
231100000167 toxic agent Toxicity 0.000 description 1
230000002588 toxic effect Effects 0.000 description 1
239000003440 toxic substance Substances 0.000 description 1
231100000419 toxicity Toxicity 0.000 description 1
230000001988 toxicity Effects 0.000 description 1
230000025033 vasoconstriction Effects 0.000 description 1
230000000304 vasodilatating effect Effects 0.000 description 1
208000003663 ventricular fibrillation Diseases 0.000 description 1

Classifications

- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives

Definitions

the invention relates to the pharmaceutical compositions, namely, to the pharmaceutical compositions for the treatment of such heart and blood vessel diseases, which are connected with blood circulation disturbances of various genesis and localization, stenocardia, myocardium infarction, arrhythmias, hypertension, myocarditis as well as low heart potency.
the proposed therapeutic composition contains known chemical substances, the use of which gives unexpected pharmacological effects. Namely, there is offered a pharmaceutical composition which contains ⁇ - butyrobetaine in a combination with 3-(2,2,2-trimethyl- hydrazinium)propionate as an active principle and pharmaceutically acceptable fillers or solvents.
3-(2,2,2-trimethyl- hydrazinium)propionate is a known preparation (Mildronate, Quaterine) (UK patent GB 2105992), the mechanism of action of which is based on limitation of carnitine biosynthesis rate and related long-chain fatty acid transport limitation through mitochondria membranes (Simkhovich B.Z., Shutenko Z.V., Meirena D.V. et al. 3-(2,2,2-trimethylhydrazinium)- propionate (THP) - a novel ⁇ -butyrobetaine hydroxylase inhibitor with cardioprotective properties. Biochem.Pharmacol. 1988, 37, 195-202).
⁇ -Butyrobetaine (actinine), from which the mammalian organism synthesises carnitine , was primarily characterised as a toxic substance which accelerates respiration, causes salivation and lacrimation, pupil dilation, vasoconstriction and heart stop in diastole (W.Linneweh, Z.Physiol.Chem., 42, 181, 1929).
⁇ -butyrobetaine is extremely low toxic (LD 50 >7000 mg/kg, s.c).
Literature lacks the data on nonsubstituted ⁇ -butyrobetaine cardiovascular effects, though it was reported (Hosein E.A., McLennan H. Pharmacological action of y-butyrobetaine. Nature, 1959, 183, 328-329) that ⁇ -butyrobetaine is a substance similar to acetyl choline with a prolonged action. However, later the same authors reported that by an error the experiments involved, instead of ⁇ -butyrobetaine, its methyl ester which in fact possesses choiinergic properties.
⁇ -butyrobetaine was characterised as a pharmacologically inert substance (E.A.Hosein, P.Proulx, Isolation and probable functions of betaine esters in brain metabolism, Nature, 1960, 187, 321-322. A.S.V.Burgen, F.Hobiger. Brit.J.Pharmacol., 4, 229 (1949), E.Strack, K.Foesterling. Z.Physiol.Chem., 1953, 295, 377).
⁇ -Butyrobetaine administration increases the level of carnitine biosynthesis in the organism serving as a substrate in this process.
Substance Dose i.v. Blood pressure Heart rate Blood flow rate mg/kg changes. % changes changes, %
the pharmaceutical composition containing ⁇ -butyrobetaine also by 2-3 times more potently affects adrenaline-induced blood vessel spasms in isolated rabbit ear than the known preparation 3 -(2,2,2- trimethylhydrazinium)propionate (Table 2).
Table 2 The pharmaceutical composition containing ⁇ -butyrobetaine also by 2-3 times more potently affects adrenaline-induced blood vessel spasms in isolated rabbit ear than the known preparation 3 -(2,2,2- trimethylhydrazinium)propionate (Table 2).
V Ventricular Ventricular Lethality occlusion tachycardy fibrillation
V Ventricular Ventricular Lethality occlusion tachycardy fibrillation
3-(2,2,2-trimethylhydrazinium)propionate and ⁇ - butyrobetaine containing pharmaceutical composition effectively protects myocardium from ischaemia-reperfusion-induced rhythm disturbances both in the prophylactic and therapeutic regimens (Tables 6 and 7).
the pharmaceutical composition containing 3-(2,2,2-trimethyl- hydrazinium)propionate and ⁇ -butyrobetaine is promising for the treatment of heart-blood vessel diseases, the efficacy of which is higher against every separate substance.
the pharmaceutical composition contains 3- (2,2,2-trimethylhydrazinium)propionate and ⁇ -butyrobetaine in the total amount of 0.5 to 40% by weight, and as a pharmaceutical acceptable solvent - distilled water, saline, glucose or buffer solution.
the active substances are administered as tablets, caplets, dragee, granules, powders or capsules they contain 3-(2,2,2-trimethylhydrazinium)- propionate and ⁇ -butyrobetaine in the total amount of 0.1 to 0.5 g in a tablet, caplet, dragee, capsule or one portion of powder or granule.

Landscapes

Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Chemical & Material Sciences (AREA)
General Health & Medical Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Medicinal Chemistry (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
General Chemical & Material Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Organic Chemistry (AREA)
Chemical Kinetics & Catalysis (AREA)
Heart & Thoracic Surgery (AREA)
Cardiology (AREA)
Epidemiology (AREA)
Urology & Nephrology (AREA)
Vascular Medicine (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Medicinal Preparation (AREA)

EP96927931A 1995-08-21 1996-08-20 Composition pharmaceutique contenant du 3-(2,2,2-trimethylhydrazinium) propionate et de la gamma-butyrobetaine, destinees au traitement des maladies cardiovasculaires Expired - Lifetime EP0845986B1 (fr)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
LVP-95-256A LV11728B (en)	1995-08-21	1995-08-21	Pharmaceutical composition
LV950256		1995-08-21
PCT/LV1996/000002 WO1997006794A1 (fr)	1995-08-21	1996-08-20	Composition pharmaceutique contenant du 3-(2,2,2-trimethylhydrazinium) propionate et de la gamma-butyrobetaine, destinees au traitement des maladies cardiovasculaires

Publications (2)

Publication Number	Publication Date
EP0845986A1 true EP0845986A1 (fr)	1998-06-10
EP0845986B1 EP0845986B1 (fr)	2003-04-02

Family

ID=19736013

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
EP96927931A Expired - Lifetime EP0845986B1 (fr)	1995-08-21	1996-08-20	Composition pharmaceutique contenant du 3-(2,2,2-trimethylhydrazinium) propionate et de la gamma-butyrobetaine, destinees au traitement des maladies cardiovasculaires

Country Status (11)

Country	Link
US (1)	US5859056A (fr)
EP (1)	EP0845986B1 (fr)
JP (1)	JP3072858B2 (fr)
AT (1)	ATE235901T1 (fr)
CA (1)	CA2229228C (fr)
DE (1)	DE69627160T2 (fr)
EA (1)	EA000472B1 (fr)
ES (1)	ES2196167T3 (fr)
LV (1)	LV11728B (fr)
UA (1)	UA44330C2 (fr)
WO (1)	WO1997006794A1 (fr)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
LV12491B (lv) *	1998-10-29	2000-12-20	Ivars KALVI��	Farmaceitiska kompozīcija
FI114538B (fi) *	2001-01-12	2004-11-15	Finnfeeds Finland Ltd	Glysiinibetaiinin käyttö verenpainetta alentavan tuotteen valmistukseen
LV12979B (en) *	2001-09-07	2003-05-20	Ivars Kalvins	Pharmaceutical composition
LV12978B (en) *	2001-09-07	2003-05-20	Ivars Kalvins	Pharmaceutical composition
JP4390134B2 (ja)	2003-11-05	2009-12-24	日本精工株式会社	ステアリング装置
LV13450B (en) *	2004-08-24	2006-11-20	Grindeks As	Novel medicinal use of meldonium and pharmaceutical compositions thereof
LV14274B (lv) *	2009-06-25	2011-03-20	Grindeks, A/S	Meldoniju saturo&scaron;s kombin&emacr;ts medic&imacr;niskais produkts
WO2010149654A1 (fr) *	2009-06-25	2010-12-29	Grindeks, A Joint Stock Company	Composition pharmaceutique de gamma-butyrobétaïne ou sel pharmaceutiquement acceptable et de meldonium ou sel pharmaceutiquement acceptable
LV14345B (lv)	2009-10-22	2011-07-20	Grindeks, A/S	4-[Etil(dimetil)amonija]butano&amacr;ts un t&amacr; izmanto&scaron;ana kardiovaskul&amacr;ro slim&imacr;bu &amacr;rst&emacr;&scaron;anai
US8940793B2 (en)	2011-04-27	2015-01-27	Jsc Grindeks	4-[(haloalkyl)(dimethyl)ammonio]butanoates and use thereof in the treatment of cardiovascular disease
BR112013027065B1 (pt) *	2011-04-27	2019-12-03	Grindeks Jsc	processo para a preparação de sais de 3-carboxi-n-etil-n,n-dimetilpropan-1amínio, compostos e seus usos
LV14848B (lv) *	2012-10-25	2015-06-20	Latvijas Organiskās Sintēzes Institūts	Farmaceitiska kompoz&imacr;cija trimetilam&imacr;na-N-oks&imacr;da l&imacr;me&ncedil;a pazemin&amacr;&scaron;anai
GB201315321D0 (en)	2013-08-28	2013-10-09	Koninklijke Nederlandse Akademie Van Wetenschappen	Transduction Buffer
GB201521101D0 (en)	2015-11-30	2016-01-13	Koninklijke Nederlandse Akademie Van Wetenschappen	Transduction buffer
CN112180013B (zh) *	2020-09-29	2022-11-15	上海脉示生物技术有限公司	用于心肌梗死诊断的肠道微生物代谢标志物组合物及其检测方法和应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
IT1198434B (it) *	1981-01-06	1988-12-21	Sigma Tau Ind Farmaceuti	Composizione farmaceutica comprendente gamma butirrobetaina per il trattamento di sindromi da carenze di carnitina
IT1210935B (it) *	1981-09-17	1989-09-29	Inst Orch Sinteza Akademi Nauk	Composizione farmaceutica per il trattamento di malattie cardiovascolari.

1995
- 1995-08-21 LV LVP-95-256A patent/LV11728B/lv unknown
1996
- 1996-08-20 DE DE69627160T patent/DE69627160T2/de not_active Expired - Lifetime
- 1996-08-20 WO PCT/LV1996/000002 patent/WO1997006794A1/fr not_active Ceased
- 1996-08-20 AT AT96927931T patent/ATE235901T1/de active
- 1996-08-20 UA UA98020919A patent/UA44330C2/uk unknown
- 1996-08-20 US US09/011,380 patent/US5859056A/en not_active Expired - Lifetime
- 1996-08-20 CA CA002229228A patent/CA2229228C/fr not_active Expired - Fee Related
- 1996-08-20 EA EA199800160A patent/EA000472B1/ru not_active IP Right Cessation
- 1996-08-20 JP JP09509171A patent/JP3072858B2/ja not_active Expired - Fee Related
- 1996-08-20 EP EP96927931A patent/EP0845986B1/fr not_active Expired - Lifetime
- 1996-08-20 ES ES96927931T patent/ES2196167T3/es not_active Expired - Lifetime

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9706794A1 *

Also Published As

Publication number	Publication date
DE69627160T2 (de)	2004-02-12
ES2196167T3 (es)	2003-12-16
WO1997006794A1 (fr)	1997-02-27
UA44330C2 (uk)	2002-02-15
EA199800160A1 (ru)	1998-08-27
EA000472B1 (ru)	1999-08-26
CA2229228A1 (fr)	1997-02-27
JPH10512286A (ja)	1998-11-24
US5859056A (en)	1999-01-12
EP0845986B1 (fr)	2003-04-02
JP3072858B2 (ja)	2000-08-07
LV11728A (lv)	1997-04-20
ATE235901T1 (de)	2003-04-15
DE69627160D1 (de)	2003-05-08
LV11728B (en)	1997-08-20
CA2229228C (fr)	2008-07-08

Legal Events

Date	Code	Title	Description
1998-04-24	PUAI	Public reference made under article 153(3) epc to a published international application that has entered the european phase	Free format text: ORIGINAL CODE: 0009012
1998-06-10	17P	Request for examination filed	Effective date: 19980220
1998-06-10	AK	Designated contracting states	Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE
2002-06-05	17Q	First examination report despatched	Effective date: 20020423
2002-09-06	GRAH	Despatch of communication of intention to grant a patent	Free format text: ORIGINAL CODE: EPIDOS IGRA
2002-10-09	RIC1	Information provided on ipc code assigned before grant	Free format text: 7A 61K 31/205 A, 7A 61P 9/00 B
2002-10-16	RIC1	Information provided on ipc code assigned before grant	Free format text: 7A 61K 31/205 A, 7A 61P 9/00 B
2002-10-16	RTI1	Title (correction)	Free format text: PHARMACEUTICAL COMPOSITION CONTAINING 3-(2,2,2-TRIMETHYLHYDRAZINIUM) PROPIONATE AND GAMMA-BUTYROBETAINE FOR THE TREATMENT OF CARDIOVASCULAR DISEASES
2003-01-11	GRAH	Despatch of communication of intention to grant a patent	Free format text: ORIGINAL CODE: EPIDOS IGRA
2003-02-15	GRAA	(expected) grant	Free format text: ORIGINAL CODE: 0009210
2003-04-02	AK	Designated contracting states	Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE
2003-04-02	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: FI Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20030402
2003-04-02	REG	Reference to a national code	Ref country code: GB Ref legal event code: FG4D
2003-04-15	REG	Reference to a national code	Ref country code: CH Ref legal event code: EP
2003-04-30	REG	Reference to a national code	Ref country code: IE Ref legal event code: FG4D
2003-05-08	REF	Corresponds to:	Ref document number: 69627160 Country of ref document: DE Date of ref document: 20030508 Kind code of ref document: P
2003-07-02	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: SE Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20030702 Ref country code: PT Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20030702 Ref country code: GR Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20030702 Ref country code: DK Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT Effective date: 20030702
2003-08-20	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: LU Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20030820
2003-08-29	REG	Reference to a national code	Ref country code: CH Ref legal event code: NV Representative=s name: DR. LUSUARDI AG
2003-08-31	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: MC Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20030831
2003-12-16	REG	Reference to a national code	Ref country code: ES Ref legal event code: FG2A Ref document number: 2196167 Country of ref document: ES Kind code of ref document: T3
2004-01-02	ET	Fr: translation filed
2004-02-06	PLBE	No opposition filed within time limit	Free format text: ORIGINAL CODE: 0009261
2004-02-06	STAA	Information on the status of an ep patent application or granted ep patent	Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT
2004-03-24	26N	No opposition filed	Effective date: 20040105
2007-10-15	REG	Reference to a national code	Ref country code: CH Ref legal event code: PFA Owner name: KALVINSH, IVARS Free format text: KALVINSH, IVARS#APARTMENT 8, MIERA 17#2169 SALASPILS (LV) $ VEVERIS, MARIS#APARTMENT 20, VEJAVAS IELA 10/2#1035 RIGA (LV) -TRANSFER TO- KALVINSH, IVARS#APARTMENT 8, MIERA 17#2169 SALASPILS (LV) $ VEVERIS, MARIS#APARTMENT 20, VEJAVAS IELA 10/2#1035 RIGA (LV)
2009-10-15	REG	Reference to a national code	Ref country code: CH Ref legal event code: PUE Owner name: GRINDEKS, A JOINT STOCK COMPANY Free format text: KALVINSH, IVARS#APARTMENT 8, MIERA 17#2169 SALASPILS (LV) $ VEVERIS, MARIS#APARTMENT 20, VEJAVAS IELA 10/2#1035 RIGA (LV) -TRANSFER TO- GRINDEKS, A JOINT STOCK COMPANY#53 KRUSTPILS STREET#1057 RIGA (LV) Ref country code: CH Ref legal event code: NV Representative=s name: BOVARD AG PATENTANWAELTE
2009-11-18	REG	Reference to a national code	Ref country code: GB Ref legal event code: 732E Free format text: REGISTERED BETWEEN 20091022 AND 20091028
2010-01-04	NLS	Nl: assignments of ep-patents	Owner name: GRINDEKS, A JOINT STOCK COMPANY Effective date: 20091014
2010-04-14	REG	Reference to a national code	Ref country code: ES Ref legal event code: PC2A
2010-08-20	REG	Reference to a national code	Ref country code: FR Ref legal event code: TP
2011-03-15	REG	Reference to a national code	Ref country code: CH Ref legal event code: PFA Owner name: GRINDEKS, A JOINT STOCK COMPANY Free format text: GRINDEKS, A JOINT STOCK COMPANY#53 KRUSTPILS STREET#1057 RIGA (LV) -TRANSFER TO- GRINDEKS, A JOINT STOCK COMPANY#53 KRUSTPILS STREET#1057 RIGA (LV)
2011-03-31	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: IT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20090820
2011-07-29	PGRI	Patent reinstated in contracting state [announced from national office to epo]	Ref country code: IT Effective date: 20110616
2011-10-31	PGFP	Annual fee paid to national office [announced via postgrant information from national office to epo]	Ref country code: IE Payment date: 20110831 Year of fee payment: 16 Ref country code: CH Payment date: 20110817 Year of fee payment: 16
2011-11-30	PGFP	Annual fee paid to national office [announced via postgrant information from national office to epo]	Ref country code: ES Payment date: 20110818 Year of fee payment: 16 Ref country code: AT Payment date: 20110705 Year of fee payment: 16
2012-12-31	PGFP	Annual fee paid to national office [announced via postgrant information from national office to epo]	Ref country code: BE Payment date: 20120709 Year of fee payment: 17
2013-03-28	REG	Reference to a national code	Ref country code: CH Ref legal event code: PL
2013-04-15	REG	Reference to a national code	Ref country code: AT Ref legal event code: MM01 Ref document number: 235901 Country of ref document: AT Kind code of ref document: T Effective date: 20120820
2013-04-30	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: CH Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20120831 Ref country code: LI Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20120831
2013-05-22	REG	Reference to a national code	Ref country code: IE Ref legal event code: MM4A
2013-06-28	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: AT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20120820
2013-07-31	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: IE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20120820
2013-08-30	PGFP	Annual fee paid to national office [announced via postgrant information from national office to epo]	Ref country code: FR Payment date: 20130703 Year of fee payment: 18
2013-10-22	REG	Reference to a national code	Ref country code: ES Ref legal event code: FD2A Effective date: 20131022
2013-10-31	PGFP	Annual fee paid to national office [announced via postgrant information from national office to epo]	Ref country code: NL Payment date: 20130805 Year of fee payment: 18 Ref country code: DE Payment date: 20130830 Year of fee payment: 18
2013-11-29	PGFP	Annual fee paid to national office [announced via postgrant information from national office to epo]	Ref country code: GB Payment date: 20130830 Year of fee payment: 18
2013-12-31	PGFP	Annual fee paid to national office [announced via postgrant information from national office to epo]	Ref country code: IT Payment date: 20130802 Year of fee payment: 18
2014-02-28	BERE	Be: lapsed	Owner name: GRINDEKS A JOINT STOCK CY Effective date: 20130831
2014-05-30	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: ES Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20120821 Ref country code: BE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20130831
2015-03-03	REG	Reference to a national code	Ref country code: DE Ref legal event code: R119 Ref document number: 69627160 Country of ref document: DE
2015-03-18	REG	Reference to a national code	Ref country code: NL Ref legal event code: V1 Effective date: 20150301
2015-04-29	GBPC	Gb: european patent ceased through non-payment of renewal fee	Effective date: 20140820
2015-04-30	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: IT Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20140820 Ref country code: NL Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20150301
2015-05-28	REG	Reference to a national code	Ref country code: DE Ref legal event code: R119 Ref document number: 69627160 Country of ref document: DE Effective date: 20150303
2015-05-29	REG	Reference to a national code	Ref country code: FR Ref legal event code: ST Effective date: 20150430
2015-07-31	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: DE Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20150303 Ref country code: GB Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20140820
2015-08-31	PG25	Lapsed in a contracting state [announced via postgrant information from national office to epo]	Ref country code: FR Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20140901

Publication	Publication Date	Title
EP0845986B1 (fr)	2003-04-02	Composition pharmaceutique contenant du 3-(2,2,2-trimethylhydrazinium) propionate et de la gamma-butyrobetaine, destinees au traitement des maladies cardiovasculaires
US4255449A (en)	1981-03-10	Method of treating abnormal lipoprote in ratios
US4194006A (en)	1980-03-18	Therapeutic application of acetyl-d,l-carnitine and other acyl derivatives of d,l-carnitine
JPH027572B2 (fr)	1990-02-19
JP2729333B2 (ja)	1998-03-18	血管拡張療法が必要とされる症状を治療するための医薬組成物
US4268524A (en)	1981-05-19	Method of treating abnormal lipoprotein ratios with acylcarnitine
WO1997006795A1 (fr)	1997-02-27	Compositions pharmaceutiques a base de gamma-butyrobetaine pour le traitement des troubles de la circulation sanguine
US5861434A (en)	1999-01-19	Compositions containing L-carnitine or an acyl L-carnitine in combination with an ace-inhibitor for the treatment of cardiovascular disorders and a method for treating cardiovascular disorders
IE51711B1 (en)	1987-03-04	Carnitine derivatives
HK1009325B (en)	1999-05-28	Composition comprising l-carnitine or acyl-l-carnitine in combination with an ace-inhibitor for the treatment of cardiovascular disorders
AU2002236340B2 (en)	2008-06-12	Pharmaceutical composition comprising gamma-butyrobetaine
CA1336961C (fr)	1995-09-12	Composition a effet durable de propafenone et de quinidine pour le traitement de maladies cardiaques
US20020002202A1 (en)	2002-01-03	Use of fumarate salt of L-carnitine or its alkanoyl derivatives in ischaemia
AU2001241031B2 (en)	2005-10-27	Composition for the prevention and/or treatment of the cytotoxic effects induced by the use of immunosuppressive agents
EP1305020B1 (fr)	2006-06-21	Utilisation de fibrates dans la preparation d'un medicament utilise dans le traitement d'insuffisance cardiaque globale
GB2140688A (en)	1984-12-05	Fatty acid containing compositions
IE51712B1 (en)	1987-03-04	Pharmaceutical compositions containing carnitine derivatives
US5326774A (en)	1994-07-05	Pharmaceutical preparation of antihypertensive, antianginal, antiarrhythmic and antiglaucomic action
JPH03115220A (ja)	1991-05-16	非心臓由来の不整脈防止薬
AU2001241031A1 (en)	2001-11-22	Composition for the prevention and/or treatment of the cytotoxic effects induced by the use of immunosuppressive agents
OGATA et al.	1972	The Effect of Fusaric Acid, Inhibitor of Dopamine β‐hydroxylase, on Reaction to Alcohol in Chronic Alcoholics: Clinical Findings